Carbamazepine

PEP Topic

Peripheral Neuropathy

Description

Carbamazepine is used alone or with other medications in the treatment of certain types of seizures. Carbamazepine also is used to treat trigeminal neuralgia (a condition that causes facial nerve pain) and is an anticonvulsant that works by reducing abnormal electrical activity in the brain. Carbamazepine is available as a tablet, a chewable tablet, an extended-release tablet, an extended-release capsule, and a suspension (liquid) to take by mouth. Carbamazepine has been studied related to chemotherapy-induced nausea and vomiting (CINV) and peripheral neuropathy.

Intervention Characteristics/Basic Study Process:

Carbamazepine was tested in the prevention of chemotherapy-induced perihpheral neuropathy (CIPN) in 10 of 40 patients receiving oxaliplatin, folinic acid, and 5-FU chemotherapy. Ten patients also received carbamazapine 200 mg orally. Carbamazepine 200–600 mg was administered orally, with doses adapted to serum levels of 3-6 mg/l starting the week prior to treatment for two days, increased dose to 600 mg orally, and then doses were titrated to meet serum levels of 3-6 mg/l. Carbamazapine was administered until the end of oxaliplatin therapy, but if CIPN symptoms continued, carbamazepine also was continued until symptoms dissipated.

Sample Characteristics:

A total of 40 pretreated patients with advanced colorectal cancer received combination chemotherapy with oxaliplatin 85 mg/m² on days 1, 15, and 29.

Folic acid 500 mg/m² and 5-FU 2,000 mg/m² were given on days 1, 8, 15, 22, 29, and 36.

Study Design:

The study was a non-randomized pilot design.

Measurement Instruments/Methods:

Weekly neurologic examinations measured vibratory sensibility of the plantar surfaces of feet and hands by a tuning fork, cold-induced symptoms, and documentation of side effects.

Neuropathy also was assessed by the World Health Organization toxicity grading scale.

Results:

No WHO grade 2-4 neuropathy was found in the patients treated with carbamazepine compared to 30% who experienced grade 2-4 neuropathy in a historical control group.

Limitations:

The study's non-randomized, non-blinded design was a limitation, as was the use of a historical comparison group.

The very small sample size of 10 participants precludes comparison of group differences.

Study Purpose:

This study evaluated the efficacy and safety of carbamazepine for the prevention of oxaliplatin-associated neuropathy in patients treated for advanced-stage colorectal cancer.

Intervention Characteristics/Basic Study Process:

Patients were randomly assigned to receive carbamazepine 200 mg orally daily, beginning six days before the first oxaliplatin via IV, with dose increases to yield a plasma level of 4-6 mg/dl. All patients received oxaliplatin 85 mg/m² via IV every two weeks, plus folinic acid 500 mg/m² via IV followed by 5-FU 2,000 mg/m² infused over 24 hours every week. A cycle consisted of six weeks of treatment and a two week rest. Groups were compared in relation to worst neurotoxicity and neurotoxicity at each cycle.

Sample Characteristics:

The study consisted of 36 total patients, with 19 assigned to the carbamazepine group and 17 to the control group.

To be included, patients had confirmed advanced-stage colorectal cancer, were 18 years of age or older, had a World Health Organization performance status of 0 or 1, and had an anticipated life expectancy of at least three months. Laboratory criteria also needed to be met.

Patients were excluded if they had preexisting neurologic diseases, had been treated with a drug that could interact with carbamazepine, had prior treatment with oxaliplatin, and were currently being treated with gabapentin, vitamin B, magnesium, or calcium.

Study Design:

The study had a randomized, controlled, multicenter phase II design.

Measurement Instruments/Methods:

Data were collected at baseline and following each treatment cycle using Levi’s Neurotoxicity Rating Scale (0–4), and peripheral neuropathy score based on sensory symptoms and examination (vibrational sense, strength, and deep tendon reflexes), each scored 0–3.

Results:

No group differences were noted in grade of neurotoxicity or in grade 3 or 4 neurotoxicity using the Levi Neurotoxicity Rating Scale for either the worst toxicity across all cycles or cycle-based comparisons. The groups did not differ in scores on the individual components of the peripheral neuropathy score or the overall peripheral neuropathy score based on worst toxicity or cycle-specific comparisons between groups. Of note, only two participants discontinued carbamazepine for CNS side effects.

Conclusions:

Because the current study was underpowered, no definitive conclusions can be drawn regarding efficacy and safety.

Limitations:

Regarding limitations, the final sample size was not adequate enough to achieve the power needed to detect differences between groups.

No data on reliability or validity for the Levi Neurotoxicity Rating Scale were provided.

Reliability and validity of the two approaches used to grade or score severity of neuropathy was not discussed.

Adherence to carbamazepine was not assessed but the plasma levels suggest that adherence was acceptable during the early phases of the study.

The results are inconsistent with a nonrandomized pilot study conducted by the same group.